The long term objective of this research program is elucidate the mechanisms of carcinogenesis by nickel compounds. The specific aims of this proposal are: (a) to investigate the inhibitory effect of manganese upon the carcinogenicity of nickel subsulfide (Ni3S2); (b) to identify the metabolic basis for the pronounced differences which have been found between the carcinogenicities of Ni3S2 and nickel sulfide (NiS); and (c) to characterize and standardize an experimental system for induction of renal carcinomas in rats by intrarenal injection of Ni3S2. The methods include: (a) carcinogenesis testing following administration of Ni3S2, NiS, Mn and other compounds to Fischer rats by intramuscular and/or intrarenal injection; (b) histological and electron microscopic investigations of pathological lesions that are associated with induction of renal carcinomas by Ni3S2; and (c) compartmental analysis of 63Ni and 35S kinetics in order to identify differences in the metabolism of radiolabelled Ni3S2 and NiS in rats. This study is providing fundamental knowledge of metal carcinogenesis, and is also furnishing information which has practical applications to assessing human hazards of carcinogenesis from nickel compounds, with particular relevance to energy research, industrial toxicology and environmental pollution.